Derivatives of 5,11-dihydrodibenzoxazepines and process therefor

ABSTRACT

This invention relates to novel derivatives of 5,11dihydrodibenzoxazepines having the formula   AND ACID-ADDITION SALTS THEREOF, WHEREIN A is lower alkylene of at least two carbon atoms, B is a basic saturated nitrogencontaining radical of less than 12 carbon atoms, and R and R&#39;&#39; each are selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy and N,N-dimethylaminosulfonyl. The compounds of this invention are therapeutically active materials which are useful hypotensive agents and for the control of the growth of tumors. In addition, they find utility as antibacterial and antifungal agents.

United States Patent [1 1 Yale et al.

[ 51' Jan. 30, 1973 [54} DERIVATIVES OF 5,11-

DIHYDRODIBENZOXAZEPINES AND PROCESS THEREFOR [75] lnventors: Harry L. Yale, New Brunswick; Francis A. Sowinski, Edison, both of [73] Assignee: E. R. Squibb & Sons, Inc., New

York,N.Y.

[22] Filed: Sept. 28, 1970 [21] Appl. No.: 76,285

Related U.S. Application Data 9 [63] Continuation-impart of Ser. No. 668,632, Sept. I8,

1967, abandoned, which is a continuation-in-part of Ser. No. 438,406, March 9, I965, abandoned.

[52] U.S. Cl. ..260/333, 260/293.58, 260/268 TR, 260/243 B, 260/247.5 R, 260/326.5 CA, 424/246, 424/248, 424/250, 424/267,

424/274, 424/244 [51] Int. Cl. ..C07d 87/54 [58] FieldofSearch ..260/333, 293.58, 368 TR 260/243 B, 260/247.5 R, 326.5 CA

[56] References Cited UNlTED STATES PATENTS l2/l962 Yale et al. ..260/333 6/1968 Yale et al. ..260/327 Primary Examiner-Norma S. Milestone Att0rney-Lawrence S. Levinson, Merle J. Smit Donald J. Perella and Burton Rodney [57] ABSTRACT This invention relates to novel derivatives of 5,11- dihydrodibenzoxazepines having the formula I lower alkoxy, trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy and N,N-dimethylamino-sulfonyl.

The compounds of this invention are therapeutically active materials which are useful hypotensive agents and for the control of the growth of tumors. In addition, they find utility as antibacterial and antifungal agents.

7 Claims, N0 Drawings DERIVATIVES OF 5,] l- DII-IYDRODIBENZOXAZEPINES AND PROCESS THEREFOR RELATED APPLICATIONS This application is a continuation-in-part of copending application Ser. No. 668,632 filed Sept. 18, 1967 and now abandoned, which in turn is a continuation-inpart of copending application Ser. No. 438,406 filed Mar. 9 1965, now abandoned.

This invention relates to new chemical compounds and, more particularly, to certain new derivatives of 5,1 l-dihydrodibenz-oxazepines.

ln U.S. Pat. No. 3,069,432, granted Dec. 18, 1962 to Yale et al., there is described a new class of chemical compounds of the formula I:

I and non-toxic acid-addition salts thereof, wherein A is lower alkylene of at least two carbon atoms, B is a basic saturated nitrogen-containing radical of less than 12 carbon atoms, and R and R are the same or different and represent hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy or N,N-dimethylaminosulfonyl. Among the suitable radicals represented by the symbol B are mentioned: (lower alkyl)amino; di(lower alkyl)amino; (hydroxy-lower alkyl)amino; di(hydroxylower alkyl)amino; and basic saturated five to six membered N-heterocyclic radicals of less than 12 carbon atoms, as exemplified by piperidyl [i.e., piperidino, 2-piperidyl, 3-piperidyl and 4-piperidyl]; (lower alkyl)piperidyl [e.g., 2, 3, or 4-(lower alkyl)piperidino or 2, 3, or 4-(N-l0wer alkyl)piperidyl]; di(lower alkyl)piperidyl [e.g., 2,4-, 2,5- or 3,5-di(lower alkyl)piperidino, or 2, 3, or 4-(N-lower alkyl- 2, 3 or 4- (lower alkyl)piperidyl]; (lower alkoxy)piperidyl; pyrrolidyl; (lower alkyl)pyrrolidyl; di(lower alkyl)pyrrolidyl; (lower alkoxy)pyrrolidyl; di(lower alkyl)pyrrolidyl; (lower alkoxy)pyrrolidyl; morpholinyl [i.e., morpholino, 2-morpholinyl and 3-morpholinyl]; (lower alkyl)morpholinyl; di (lower alkyl)morpholinyl; (lower alkoxy)morpholinyl; thiamorpholinyl; (lower alkyl)thiamorpholinyl; di(lower alkyl)thiamorpholinyl; (lower alkoxy)thiamorpholinyl; piperazyl; (lower alkyl)piperazyl (e.g., 4 -methylpiperazino); di(lower al kyl)piperazyl; (lower alkoxy)piperazyl; (hydroxy-lower alkyl)piperazyl [e.g., 4-(2-hydroxyethyl)piperazino]; (lower alkanoyloxy-alkyl)piperazyl [e.g., 4-(2-acetoxyethyl)piperazino]; (hydroxy-lower alkoxy-lower alkyl)piperazinyl [e.g., 4-(2-hydroxyethoxyethyl)piperazino]; and (carbo-lower alkoxy)piperazyl [e.g., 4-(2carbomethoxy, carbe-thoxy, or carbopropoxy)piperazino].

This patent further teaches that such compounds can be formed by interacting a compound of the formula II:

wherein R and R are as hereinbefore defined, with an aminoalkyl halide of the formula: B--A(halo), wherein A and B are as hereinbefore defined, in the presence of a basic condensation reagent such as sodium hydride.

It has now been found that if this reaction is conducted using an excess of the basic condensation agent and an equivalent excess of aminoalkyl halide, for example, at least 2 moles of each per mole of compound of the formula ll, a second compound is also formed.

This second compound, which represents the new compounds of this invention, are of the formula III:

R a, Q

III

and salts thereof, wherein A, B, R and R are as hereinbefore defined.

As to the salts, those coming within the purview of this invention include the acid-addition salts, particularly, the non-toxic acid-addition salts. Acids useful for preparing the acid-addition salts, include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as oxalic, maleic, tartaric, citric, acetic, and succinic acid.

The new compounds of this invention (the compounds of formula III and their non-toxic acid-addition salts) are therapeutically active compounds which are utilizable both as hypotensive agents and for the control of the growth of tumors, such as Sarcoma tumors, in mice. For these purposes they may be administered orally or parenterally to various animal species, such as rats, monkeys, dogs, horses, and the like, in conventional dosage forms such as tablets, capsules, elixirs, injectables, and the like, by incorporating the appropriate dose of the compound with carriers according to acceptable pharmaceutical practice.

For use as hypotensive agents in animal species such as the above, the suitable dosage would range from 7 to 12 mg./kg. of body weight daily.

For use in control of tumor growth in animal species such as the above, the suitable dosage would range from l0 to 60 mg./kg. of body weight daily.

In addition the above compounds of the instant invention are useful as antibacterial and antifungal agents, for instance against such organisms as Mycobacterium tuberculosis, Trichophyton mentagrophytes, Fusarium bulbigenum, and the like. As such they may be employed as antiseptics or disinfectants for the control or elimination of airborne or environmental microorganisms, e.g., in sprays, aqueous solutions,

emulsions, or suspensions of up to about 10 percent concentration.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 -[o-{o-[2-(Dimethylamino)ethoxy]-N-[2- (dimethylamino)-ethyl]-anilino]benzyl]-5,l1- dihydrodibenz[b,e] 1 ,4]oxazepine To 197.6 g. of 5,1l-dihydrodibenz[b,e][l,4]oxazepine in 2 liters of dry tetrahydrofuran is added in small portions a total of 60 g. of a 50 percent dispersion of sodium hydride in mineral oil. The mixture is then stirred for 16 hour, 161.2 g. of Z-dimethylaminoethyl chloride is added dropwise, and the whole stirred and refluxed for 2 hours. The mixture is allowed to cool to room temperature and treated again with 48 g. of 50 percent sodium hydride and 107 g. of 2- dimethylaminoethyl chloride. Subsequently, the whole is stirred and refluxed for 5 hours, filtered, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 1 liter of ether and the ether solution extracted successively with 1 liter and then with 500 ml. of percent aqueous phosphoric acid. The acid extracts are treated with an excess of solid potassium carbonate and the crude base, about 275.6 g., isolated via ether extraction. The crude base is subjected to distillation to yield about 145.6 g. of product 5-(2- dimethylaminoethyl)-5,l l-dihydrobenz[b,e][1,4]oxazepme.

The residue from the distillation solidifies on cooling. Recrystallization from acetone gives 5-[o-[-[2- (dimethylaminoethoxy1-N-[2-(dimethylamino)ethyl] anilino]-benzyl]-5,l 1-dihydrodibenz[ b,e][1,4]oxazepine, m.p. about 123-125.

Anal. Calcd. for C l-1 N 0 C, 76.08; H, 7.51; N,

10.44 ;N.E. 268.4; Molecular Wt., 536,72. Found: C, 75.80; H, 7.78; N, 10.79; N.E. (HCIO,),

273.5; Molecular Wt. (osmometrically), 541.0.

EXAMPLE 2 5-[o-[o -[3-(Dimethylamino)propoxy]-N-[3- (dimethylamino)-propyl]anilino]benzyl]-5,1 ldihydrodibenz[b,e]1,4]-oxazepine Following the procedure of Example 1 but substituting an equivalent amount of B-dimethylaminopropyl chloride for the 2-dimethylaminoethyl chloride, 5-[o-[ o' -[3-(dimethylamino)pro-poxy]-N-[3- (dimethylamino )propyl]anilino]benzyl]-5,1 dihydrodi-benz[b,e][1,4]oxazepine is formed.

EXAMPLE 3 5-[o-[ o -[2-(dimethylamino)ethoxy1-N-[2- dimethylamino)-ethyl]-anilino]benzyl]-5,l 1-

dihydrodibenz[b,e]1,4]oxazepine hydrochloride To 5- [o-[o -[2-(dimethylamino)ethoxy]-N-[2- (dimethylamino)-ethyl]anilino]benzyl]-5,l 1- dihydrodibenz[b,e}l,4]oxazepine in dry ether is added dropwise, with ice cooling, a solution of dry hydrogen chloride in dry ether. The precipitate which forms is allowed to granulate and then is rapidly filtered under anhydrous conditions. The hygroscopic product is freed of solvent in vacuo to give the hydrochloride salt as an amorphous product.

EXAMPLE 4 7Chloro -5-[o-[5-chloro-2[2-(dimethyl)ethoxy]-N-[2- (dimethylamino)ethyl]-anilino]benzyl-5 ,1 l-

dihydrodibenz[b,'e][1,41-oxazepine Following the procedure of Example 1 but substituting an equivalent amount of 7-chloro-5,l ldihydrodibenz[b,e][1,4] oxazepine for the oxazepine reactant, the above-identified product is obtained.

EXAMPLE 5 5-[o[o-[2-(Dimethylamino)ethoxy]-N-[ 2- dimethylamino)ethyl]-5-(trifluoromethyl)anilino] benzyl-5,1 1-dihydro-7-(trifluoromethyl)-dibenz[b,e ][1,4]oxazepine Following the procedure of Example 1 but substituting an equivalent amount of 7-trifluoromethyl-5,l1- dihydrodibenz(b,e][l,4]-oxazepine for the oxazepine reactant, the above-identified product is obtained.

EXAMPLE 6 EXAMPLE 7 5,1l-Dihydro-5-1o-[o-[3-(4- methylpiperazino )propoxy]-N-[ 3- (4- methylpiperazino)propyl ]nilinolbenzyl]dibenz[b,e]

[ 1,4]oxazepine Following the procedure of Example 1 but substituting an equivalent amount of 3-(4-methylpiperazino)propyl chloride for the 2 dimethylaminoethyl chloride, the above-identified product is formed.

EXAMPLE 8 Following the procedure of Example 1 but substituting an equivalent amount of 3-[4-(2-hydroxyethyl)piperazino]propyl chloride for the 2- dimethylaminoethyl chloride, the above-identified product is formed.-

EXAMPLES 9-24 Following the procedure of Example 1 but substituting for 5,1 1-dihydrodibenz[b,e][1,4]oxazepine the oxazepine compound indicated in Column 1, and substituting for 2-dimethylaminoethyl chloride the com- 5' 6 pound, B-A-Cl, indicated in Column ll, there is obchlorobromoalkane in 500 ml of dry chloroform there mined the cimpcllund indicated in g g fl The is added dropwise 1.0 mole of the anhydrous nitrogen compounds 0 Co umn are prepare y re uxmg an base in 250 ml of chloroform; when the addition is amine, BH, with an a, w-chlorobromoalkane, Cl-

A Br, in dry hl f The procedure is follows; 5 complete the mixture is refluxed for three hours to give to a solution containing 1.0 mole of the a, wthe BAClcompound ofColumn ll.

1 II III Oxazopine BA--Cl Product Lon;

Jill:

EXAMPLE 25 (Comparative) i y opropyl) 5,11 Dihydrodibenz ,e] [1,4] Oxazepine.

A stirred mixture of 0.04 mole of 5,11- dihydrodibenz-[b,e][1,4]oxazepine, 0.047 mole of a 50 percent sodium hydride dispersion in mineral oil, and 200 ml. of dry xylene is heated under reflux for one hour and cooled. 3-Dimethylaminopropyl chloride (0.06 mole) is then added dropwise and the resulting mixture heated under reflux for 5 hours. The reaction mixture is then filtered, cooled and extracted with two 200 ml. portions of 5 percent hydrochloric acid. The combined acid extracts are made strongly basic with solid potassium carbonate and extracted with ether. After drying, the ether is removed to give about 13.3 g. of residue. Distillation gives a yellow oil, B.P. about l38-l43(0.15 mm).

Both the residue and the distillate are tested separately for the presence of 5-[0-[0-[3- (dimethylaminopropoxy]-N-[3- (dimethylamino)propyllanilinolbenzyl]-5,l 1- dihydrodibenz[b,e]l,4]oxazepine, but each is found to be free of said compound. This shows that the foregoing compound is not formed when the sodium hydride and aminoalkyl halide are not present in molar quantities at least twice that of the oxazepine compound.

EXAMPLE 26 (Comparative) 5 (2 Dimethylaminoethyl) 5,11 Dihydrodibenz [b,e] [1,4] Oxazephine Maleate.

To a solution of 0.05 mole of 5,1 1- dihydrodibenz[b,e][1,4]oxazepine in 100 ml. of dry tetrahydrofuran, under nitrogen, is added 24 ml. of 2- dimethylaminoethyl chloride followed by 0.07 mole of a 50 percent dispersion of sodium hydride in mineral oil. The mixture is refluxed for four hours, cooled and filtered. The filtrate is concentrated to dryness and the residue is dissolved in acetone and an acetone solution of maleic acid is added. Ether is added to crystallize the product, 5-(2-dimethylaminoethyl)-5,l 1- dihydrodibenz[b,e]1,4]oxazepine maleate.

Both the foregoing product and the mother liquor are tested separately for the presence of 5-[0-[0-[2- (dimethylamino)ethoxy]-N-[2-(dimethylamino)ethyl] anilino]benzyl]5,ll-dihydrodibenz[b,e][1,4]oxazepine, but each is found to be free of said compound. This shows that the foregoing compound is not formed when the sodium hydride and aminoalkyl halide are not present in molar quantities at least twice that of the ox- I azepine compound.

What is claimed is: 1. A compound selected from the group consisting of bases of the formula atoms, B is a basic saturated nitrogen-containing radical of less than 12 carbon atoms selected from the group consisting of (lower alkyl)amino; di(lower alkyl)amino; (hydroxy-lower alkyl)amino; di(hydroxylower alkyl)amino; and basic saturated five to six membered N-heterocyclic radicals of less than 12 carbon atoms selected from the group consisting of piperidyl, (lower alkyl)piperidyl, di(lower alkyl)piperidyl, (lower alkoxy)-piperidyl, pyrrolidyl, (lower alkyl)pyrrolidyl, di(lower alkyl)-pyrrolidyl, (lower alkoxy)pyrrolidyl, morpholinyl, (lower alkyl)morpholinyl, di(lower alkyl)-morpholinyl, (lower alkoxy)morpholinyl, thiamorpholinyl, (lower alkyl)thiamorpholinyl, di(lower alkyl)thiamorpholinyl, (lower alkoxy)thiamorpholinyl, piperazyl, (lower alkyl)piperazyl, di(lower alkyl)piperazyl, (lower alkoxy)piperazyl, (hydroxy-lower alkyl)piperazyl, (lower alkanoyloxy-alkyl)piperazyl, (hydroxy-lower alkoxy-lower alkyl)piperazinyl, and (carbo-lower alkoxy)piperazyl, and R and R are each selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy and N,N-dimethylaminosulfonyl; and non-toxic acid-addition salts thereof.

2. A compound in accordance with claim 1 having the name 5-[o -[o -[Di(lower alkyl)amino](lower alk0xy)]-N-[di-(loweralkyl)amino](lower alkyl)]anilino]benzyl]-5-N-dihydrodibenz [b,e][ 1,4]oxazepine.

3. A non-toxic acid-addition salt of the compound of claim 2.

4. A compound in accordance with claim 1 having the name 5-[o -[o [2-(Dimethylamino)ethoxy] -N-[2- (dimethylamino) ethyl]anilino]benzyl]-5 ,1 l dihydrodibenz[b,e][l ,4loxazepine.

5. A non-toxic acid-addition salt of the compound of claim 4.

6. The hydrochloride salt of the compound of claim 4.

7. A method of preparing a compound of claim 1 which. comprises adding slowly to an oxazepine compound of the formula Nll mg UNITED STATES PATENT OFFICE CERTIFICATE OF (:ORRECTIQN Patent No. 3,714, 192 Dated January 30 1973 Inventofls) Harry L Yale et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 34, "yOl'ower" should read ylower-.

Column 3, line 33, "dihydrobenz" should read -dihydrodibenz--.

Column 3, line 36, "5[o-[-[2" should read 5-[0-[0-[2- Column 3, line 41, "536,72" should read --536.72--. Column 3, line 66, [b,e]l,4] should read [b,e] [l,4]-.

Column 4 line 8 "2[2(dimethyl) should read 2-[2- (dimethylamino)-. Column 4, line 30, "ethoxyl" should read -vethoxy-. Column 4-,--line 41', "5-] o" should read 5 [o--'. Column 4, line 43, "nilino" should read anilino. Column 4, line 54, "ropoxy" should read -'-propo iy--. Column 4, I line 55, "ropyl" should read -propyl-.

Column 13, line 40, "Oxazephine" should read --Oxazepi'ne--. Column 13, line 53, [b,e]l-,-4] should read -[b,e] [l,4]--.

Signed and sealed this 3rd day. of July 1973.

(SEAL) Attest:

EDWARD M.F LETCHER,JR. I Rene Tegtmeyer I Attesting Officer Acting Commissioner of Patents 

1. A compound selected from the group consisting of bases of the formula
 2. A compound in accordance with claim 1 having the name 5-( o -( o -(Di(lower alkyl)amino)(lower alkoxy))-N-(di-(lower alkyl)amino)(lower alkyl))anilino)benzyl)-5-N-dihydrodibenz (b, e)(1,4)oxazepine.
 3. A non-toxic acid-addition salt of the compound of claim
 2. 4. A compound in accordance with claim 1 having the name 5-( o -( o (2-(Dimethylamino)ethoxy)-N-(2-(dimethylamino) ethyl)anilino)benzyl)-5,11-dihydrodibenz(b,e)(1,4)oxazepine.
 5. A non-toxic acid-addition salt of the compound of claim
 4. 6. The hydrochloride salt of the compound of claim
 4. 